Vps53-KO Mouse

Vps53, a subunit of the Golgi-associated retrograde protein (GARP) complexes, is involved in the retrograde pathway recycling endocytic vesicles to the Golgi [6]. The GARP complex mediates retrograde trafficking from the endosome to the trans-Golgi network, which is crucial for intracellular cholesterol transport, sphingolipid homeostasis in lysosomes and some cell-morphological regulations [2,7].

Mutations in Vps53 have been associated with various human diseases. In colorectal cancer, Vps53 is downregulated. Overexpression of Vps53 can suppress the proliferation, migration, and invasion of CRC cells, and accelerate apoptosis and autophagy by upregulating Beclin 1 and LC3BII, suggesting its potential as a therapeutic target [1]. In hereditary spastic paraparesis (HSP), a homozygous pathogenic variant in Vps53 was identified in two siblings with complicated HSP, expanding the phenotype of VPS53-related disease [2]. Also, Vps53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2) in individuals of Jewish Moroccan ancestry [3]. A case of a neonate with Vps53 pathogenic variants exhibited liver disease and deafness along with classic features of pontocerebellar hypoplasia type 2E (PCH2E), indicating liver involvement might be an under-recognized feature of PCH2E [4]. In endometriosis, GZFLW was found to induce apoptosis of ectopic endometrial stromal cells via promoting Vps53 protein stability [5]. In Candida albicans, deletion of Vps53 (a GARP complex subunit) severely impaired filamentation in response to diverse cues [7].

In conclusion, Vps53 is essential for endosome-to-Golgi retrograde trafficking and maintaining lipid homeostasis. Its dysregulation is implicated in multiple human diseases such as colorectal cancer, neurodegenerative disorders like HSP and PCCA2, and potentially liver-related issues in PCH2E. Understanding Vps53 function through genetic models could provide insights into disease mechanisms and potential therapeutic strategies.